Indazole derivatives



United States Patent 0 3,145,215 INDAZOLE DERIVATIVES Frederick K.Kirchner, Bethlehem, N.Y., assiguor to Sterling Drug Inc, New York,N.Y., a corporation of Delaware No Drawing. Filed Dec. 19, 1961, Ser-No. 160,663 12 Ciaims. (Cl. 260--310) This invention relates to basicesters and amides.

The invention herein resides in the concept of compositions of matterhaving a molecular structure obtained when a 3-indazolecarbonyl group isjoined through an --O or NH- bridge to the known types oftertiaryamino-lower-alkyl groups and their quaternary ammoniumderivatives, together with a process for physically embodying suchconcept, and the utility inherent in the embodiments so produced.

The compounds of the invention are compounds of the generalized formulaW-CO--XalkN:B, wherein W represents a S-indazole moiety, X represents amember of the group consisting of oxygen and imino, alk represents amember of the group consisting of alkylene having from two to six carbonatoms and having the free valences on different carbon atoms andoxa-alkylene having from four to eight carbon atoms and N=B represents atertiaryamino group, and quaternary ammonium salts represented by thegeneralized formula WCOXalk-Q+An*, wherein Q represents quaternaryammonium, An represents an anion, and W, X, and alk have the samemeaning as given above.

The symbol W, as used herein, represents an unsubstituted indazole or anindazole group substituted in the benzene ring by one or moresubstituents inert to the reaction conditions and reagents used in theprocess for preparing the compounds. Such inert substituents include,without limitation, lower-alkyl, lower-alkoxy, lower-alkylmercapto,lower-alkylsulfinyl, lower-alkylsulfonyl, halogen, nitro, dialkylaminoand trifluoromethyl groups; as Well as additional hydrogen atoms, inwhich latter case the corresponding tetraliydro compounds result; and,the 3-indazolegroup can also include a lower-aliphatic hydrocarbon,monocarbocyclic aryl substituted lower-aliphatic hydrocarbon ormonocarbocyclic aryl substituent on either of the nitrogen atoms of thepyrazole ring.

A particular aspect of the invention relates to basic esters and amideshaving, in the free base form, the formula Formula I and in the cationform the formula Formula 11 wherein Y is a member of the groupconsisting of hydro- Patented Aug. 18, 1964 gen, lower-alkyl,lower-alkoxy, lower-alkylmercapto, lower-alkylsulfinyl,loWer-alkylsulfonyl, nitro, halogen, trifluoromethyl, and amino; R is amember of the group consisting of hydrogen, lower-aliphatic hydrocarbon,phenyl and benzyl; X is a member of the group consisting of O and NH;alk is a member of the group consisting of alkylene having from two tosix carbon atoms and having the free valences on diiierent carbon atomsand oxaalkylene having from four to eight carbon atoms; and N=B is amember of the group consisting of di-(loweralkyl)amino, l-pyrrolidinyl,lower-alkylated-l-pyrrolidinyl, piperidino, lower-alkylated-piperidino,morpholino, lower-alkylated-morpholino, thiomorpholino,loWer-alkylated-thio-morpholino, l-piperazinyl, 4-methyl-1-piperazinyl,4-phenyl-l-piperazinyl, 1-hexamethyleniminyl, and 1-heptamethyleniminyl; and Z is lower-alkyl, lower-alkenyl ormonocarbocyclic arylmethyl. The free bases of Formula I react withorganic and inorganic acid to form acid-addition salts which are thefull equivalents of the free bases.

In Formula I above, alk is a divalent saturated hydrocarbon bridge whichjoins the X atom and the nitrogen atom of N=B and intervenes two to fivecarbon atoms between the X and nitrogen atoms, and contains a total oftwo to six carbon atoms or alk is an oxaalkylene group having from fourto eight carbon atoms. Thus, alk includes for example radicals such asCH CH CH(CHH )CH CH CH CH CH(CH )CH CH CH CH and the like whenrepresenting a divalent saturated hydrogen bridge and CH CHEHQCH OCHCH(CH )CH and the like when representing an oxaalkylene radical.

The radical Y in Formula I above represents a hydrogen atom or aloWer-alkyl, lower-alkoxy, lower-alkylmercapto, lower-alkylsulfinyl,lower-alkylsulfonyl, nitro, halogen, trifiuoromethyl or amino radical.The Y substituent lower-alkyl, lower-alkoxy, lower-alkylmercapto,lower-alkylsulfinyl and lower-alkylsulfonyl radicals have preferablyfrom one to about six carbon atoms, thus including such radicals asmethyl, ethyl, propyl, isopropyl, butyl, sec.- butyl, pentyl, hexyl andthe like for lower-alkyl; methylmercapto, ethylmercapto,isopropylmercapto, n-hexylmercapto and the like for lower-alkylmercapto,methylsulfinyi, ethylsulfinyl, propylsulfinyl, pentylsulfinyl and thelike for lower-alkylsulfinyl; methylsulfonyl, ethylsulfonyl,n-butylsulfonyl and the like for lower-alkylsulfonyl; and methoxy,ethoxy, propoxy, butoxy, isobutoxy, pentoxy, hexoxy and the like forlower-alkoxy. The halogen can be any of the halogens fluorine, chlorine,bromine or iodine.

The radical N=B in Formula I above is a basic, aliphatic-typedisubstituted amino radical which contains 212 carbon atoms andincludes: di-(lower-alkyl)amino wherein the two lower alkyl radicals arethe same or ditierent, and each lower alkyl contains from one to sixcarbon atoms, for example dimethylamino, diethylamino, ethylmethylamino,isopropylmethylamino, diisopropylamino, ethyl-n-propylamino,di-(n-butyDamino, di-(nhexyl)amino, and the like; piperidino;lower-alkylatedpiperidino, that is piperidino bearing methyl and/ orethyl substituted on the carbon atoms thereof, for exampleZ-methylpiperidino, 3-ethylpiperidino, 4-methylpiperidino,2-methyl-4-ethylpiperidino, 2,6-dimethylpiperidino, and the like;morpholino; loWer-alkylated-morpholino, that is morpholino bearingmethyl and/or ethyl substituted on the carbon atoms thereof, for example2,6-dimethylmorpholino, 3-ethylrnorpholino, Z-methyl-S-ethylmorpholinoand the like; thiomorpholino; lower-alkylated-thiomorpholino, that isthiomorpholino bearing methyl and/or ethyl substituted on the carbonatoms thereof, for example 2-methylthiomorpholino,3-etliylthiomorpholino, 2,6-dirnethylthiomorpholinyl and the like;l-pyrrolidinyl; lower-alkylated-l-pyrrolidinyl, that is l-pyrrolidinylbearing methyl and/or ethyl substituted'on the carbon atoms thereof forexample 2-methyl-l-pyrrolidinyl, 3-ethyl-1- pyrrolidinyl,3-methyl-4-ethyl-i-pyrrolidinyl, 2,5-dimethyl-l-pyrrolidinyl, and thelike; l-hexamethyleniminyl; and l-heptamethyleniminyl. I

It will be understood of course that Formula I above represents the freebase form of the compounds and Formula' 11 represents the quaternaryammonium salts'of the new bases when Z is lower-alkyl, lower-aikenyl ormonocarbocyclic arylmethyl. As is readily apparent, the acidadditionsalts (Z H) and the quaternary ammonium compounds possess the samestructural nucleus as the bases, and the structure of the bases thusconstitutes the common characteristic feature of the three forms of thebasic esters and amides of the invention.

The quaternary ammonium salts of Formula II are obtained by the additionof lower-alkyl, lower-alkenyl, lower-alkynyl or monocarbocyclicarylmethyl esters of inorganic acids or organic sulfonic acids andhaving a molecular weight less than about 200 to the free base form ofFormula 1. Thus Z in Formula II includes lower-alkyl containing from oneto six carbon atoms, lower-alkenyl containing from three to six carbonatoms and monocarbocyclic arylmethyl containing seven to twelve carbonatoms. The quaternizing esters, which form a well-known class in thequaternary ammonium art, include such compounds as methyl chloride,methyl bromide, methyl iodide, ethyl bromide, propyl chloride, n-hexylchloride, allyl chloride, allyl' bromide, propargyl bromide, methylsulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, benzylchloride, benzyl bromide, pnitrobenzyl chloride, m-methoxybenzylbromide, p-isopropylbenzyl chloride, o-chlorobenzyl chloride, and thelike.

The compounds of the invention in free base form (Formula I) areproduced by several different methods dependings on the particular basicester or amide desired. The procedure of general applicability consistsin interacting a tertiary-aminoalkylamine or tertiary-aminoalka- 1101having the formula H-XAlkN=B wherein X, Alk and N:B have the meaningsgiven above with the known diindazolo[2,3-a,2,3-d]pyrazine-7,l4-dionehaving the formula or its Bz-substituted derivatives and which acts asan acylating agent by virtue of the rupture of bonds indicated by thedotted lines in the above formula. The reaction is carried out underanhydrous conditions in an inert solvent as for example, benzene,toluene, xylene, chloroform, carbon tetrachloride or the like, and takesplace at temperatures between about 50 C. and about 150 C., and the bestmode for carrying out the reaction consists of selecting a solvent thatboils in this range and conducting the reaction at the refluxtemperature.

The diketopiperazine derivatives of indazole illustrated by the formulaabove are produced by the action of thionyl chloride on an appropriateindazole-3-carboxylic acid whereby, in effect, a molecule of water isremoved from each of two indazole molecules which then condense witheach other.

Another method for preparing the compounds of the invention comprisesreacting an appropriately substituted lower-alkyl 3-indazolecarboxylatewith a tertiary-aminoloWer-alkylamine or a tertiary-amino-lower-alkanolunder conditions conventionally employed for amidation or esterificationof carboxylic acids and their derivatives.

The intermediate substituted lower-alkyl 3-indazolecarboxylates are aknown class of compounds which can be prepared either by treatment ofselected hydrazones of lower-alkyl o-nitrophenylglyoxylates with alkalior from isatin and its derivatives.

The quaternary ammonium salts of Formula II are prepared in conventionalfashion by interacting the free base and the quaternizing ester, eitheralone or in an inert organic solvent. Heating may be used to facilitatethe reaction, but the quaternary salt formation usually takes placereadily at room temperature. The quaternary ammonium salt separatesdirectly or can be obtained by suitable concentration of the reactionsolution or removal of the solvent. When the anion in a desiredquaternary ammonium salt is the anion of a' Weak acid, and it is notordinarily possible to employ direct quaternization, conversion of onequaternary ammonium salt to another in which the anion is different iscarried out in the usual general fashion. Thus, a quaternary ammoniumsalt containing an anion which forms a water-insoluble silver salt isobtained by direct quaternization and then reacted with silver hydroxidein aqueous medium to form the corresponding quaternary ammoniumhydroxide, the original anion being removed as a precipitate. Thequaternary ammonium hydroxide solution produced in this fashion is thenneutralized with the appropriate acid, either Weak or strong, to producethe desired new quaternary ammonium salt in which the anion is diiferentfrom that of the original salt. I

The acid-addition salt forms of the basic esters and amides of theinvention are conveniently obtained by interacting the free bases withone equivalent of an organic or inorganic acid. The acid moieties oranions in these salt forms are in themselves neither novel nor criticaland therefore can be any acid anion or acid-like substance capable ofsalt formation with the free base form of the compounds.

Compounds of this invention which were prepared as described in thefollowing examples were found to be hypotensive agents. Thus, whentested in bilaterally encapsulated renal hypertensive rats having anelevated systolic blood pressure ranging between 1.62 and 193', theyproduced a reduction in systolic blood pressure ranging from 12 to 40mm. of mercury. The results obtained for each of the indicated compoundswere as follows: N-(2- dimethylaminoethyl)-3-indazolecarboxamide, 21, 35and 38 mm. Hg at 1.25, 5 and 10 mg./kg. respectively; N-(3-diethylaminopropyl)-3-indazolecarboxamide, 12 and 20 mm. Hg at 1.25 and5 mg./kg. respectively; N-(Z-dimethylaminoethyl)4,5,6,7-tetrahydro-3-indazolecarboxamide, 33 and 25 mm. Hg at 2 and 8mg./kg. respectively; N-[2-(l-piperidyl)ethyl]-3-indazolecarboxamide, 14and 28 mm. Hg at 2 and 8 mg./kg. respectively; N-[2-(4- methyll-piperazinyl)ethyl]-3-indazolecarboxamide, 18 mm. Hg at 2 mg./kg.; andN-(Z-diethylaminoethyl)-3- indazolecarboxamide, 27 and 20 mm. Hg at 2.5and 5 mg./kg. respectively.

The structures of the compounds of this invention followed from themethods of synthesis which were used and from the elementary analyses ofthe products ob tained.

The invention is illustrated by the following examples without, however,being limited thereto.

EXAMPLE 1 N-(Z-Dimethylaminoethyl) -3-Indaz0lecarb0xamide To a solutionof 14.4 g. of diindazolo[2,3-a,2,3'-d]- pyrazine-7,14'dione in 150 ml.of dry benzene was added dropwise 32.5 ml. of Z-dime-thylaminoethylaminewith stirring. The mixture was refluxed for one-half an hour and thesolid which separated was collected by filtration and washed with water.After recrystallization from nhexane there was obtained 26.4 g. ofN-(Z-dimethylaminoethyl)-3-indazolecarboxamide, M.P. 117-119 C. (corn).

Analysis.-Calcd. for C H N O: C, 62.05; H, 6.94; N, 24.12. Found: C,62.00; H, 6.94; N, 23.78.

The free base, N-(Z-dimethylaminoethyl)-3-indazolecarboxamide, wasconverted into its p-toluenesulfonate salt by solution in benzenefollowed by the addition of methyl p-toluenesulfonate. The oil whichseparated solidified upon cooling and the solid collected by filtration.Recrystallization from absolute ethanol gave white crystals of3-(N-dimethylaminoethyl)indazolecarboxarnide methyl toluenesulfonate,M.P. 234-236 C. (corn).

Analysis.-Calcd. for C H N O S: C, 57.40; H, 6.26; S, 7.66. Found: C,57.51; H, 6.12; S, 7.72.

EXAMPLE 2 3-Diethylaminopropyl-S-Indazolecarboxylate Hydrochloride Asolution of 2.9 g. of 3-diethylamino-l-propanol in 20 ml. of toluene wasadded dropwise with stirring to a refluxing suspension ofdiindazolo[2,3-a,2,3'-d]pyrazine- 7,14-dione in 200 ml. of toluene. Themixture was refluxed for two hours then cooled to room temperature tocause the separation of a dark gum. The supernatant was decanted and thegum treated with ethereal hydrochloric acid. The solvent was againdecanted and the tack-like gum refluxed with dry acetone. The solidwhich precipitated was removed by filtration and ether added to thefiltrate to cause the separation of a tan solid which was collected byfiltration. Recrystallization from an ethanolether mixture gave 2.7 g.of 3-diethylaminopropyl-3-indazolecarboxylate hydrochloride, M.P.147-150 C. (corn).

AnaZysz's.Calcd. for C H ClN O Cl, 11.38; N, 13.48. Found: Cl, 11.27; N,13.40.

EXAMPLE 3 N -(2-Dimethylamin0ethyl -4,5,6,7-Tetrahydr0-3-Indaz0lecarb0xamide A mixture of 10 g. oftetrahydroindazole-3-carboxylic acid and 25 ml. of thionyl chloride washeated until solution was complete. The excess thionyl chloride wasallowed to evaporate and the resulting solid taken up in toluene. Afterevaporation to dryness under reduced pressure ml. ofdimethylaminoethylamine were added and the suspension heated until aclear solution resulted. The excess solvent and amine were removed bydistillation under reduced pressure, and the residue dissolved in a 5%sodium bicarbonate solution. Extraction with benzene followed byevaporation of the solvent gave a solid which was recrystallized from abenzene-hexane mixture. There was thus obtained 8.7 g. ofN-(Z-dimethylaminoethyl) 4,5,6,7-tetrahydro 3 indazolecarboxamide, M.P.115-116 C. (corn).

Analysis.-C-alcd. for C H N O: C, 60.99; H, 8.53; N, 23.71. Found: C,61.25; H, 8.33; N, 23.93.

The general procedures described in Examples 1, 2 and 3 were used toprepare the following compounds illustrative of the invention:

3-(l-piperidyD-propyl-3-indazolecarboxylate hydrochloride, M.P. l73178C. (corr.),byreacting diindazolo[2,3- a,2,3-d]pyrazine-7,14-dione with3-(l-piperidyl)-1-propanol followed by treatment with ethereal hydrogenchloride.

N (3-dimethylaminopropyl) 3 indazolecarboxamide, M.P. 92 C. (corr.), byreacting diindazolo[2,3-a,2,3- d]-Py1aZine-7,14-dione with3-dirnethylaminopropylamine.

N (3 diethylaminopropyl) 3 indazolecarboxamide, M.P. 8293 C. (corr.), byreacting diindazolo [2,3-a,2,3- d]-pyrazine-7,14-dione with3-diethylaminopropylamine.

N (l hexamethyleniminylethyl) 3 indazolecarboxamide, M.P. 126l27 C.(corr.), by reacting diindazolo[2, 3-a,2,3-d]-pyrazine-7,14-dione with1-hexamethylenimin lyethylamine.

N (1 hexamethyleniminylethyl) 3 indazolecarboxamide methylp-toluenesulfonate, M.P. l84185 C. (corr.), by reactingN-(l-hexamethyleniminylethyl)-3-ir1- dazolecar-boxarnide with methylp-toluenesulfonate.

Dimethylaminoethyl 4,5,6,7 tetrahydro 3 indazolecarboxyla-te,- M.P.114ll5 C. (corr.), by reacting 1,2,3, 4,8,9,10,11octahydroindazolo[2,3,a-2',3'-d]pyrazine 7, 14-dione withdimethylarninoethanol.

Dimethylaminoethyl 4,5,6,7 tetrahydro 3 indazolecarboxylate methylp-toluenesulfonate, M.P. 211-212 C. (corr.), by reactingdimethylaminoethyl 4,5 ,6,7-tetrahydro- 3-indazolecarboxylate withmethyl p-toluenesulfonate.

Diethylaminoethoxyethyl 3 indazolecarboxylate hydrochloride, M.P. 108109C. (corr.), by reacting diinda-' zolo[2,3-a,2',3-d]pyrazine-7,14-dionewith diethylaminoethoxyethyl alcohol followed by treatment with etherealhydrogen chloride.

N-(dimethylaminoethyD-S-bromo 3 indazolecarboxamide, M.P. 172173 C.(corr.), by reacting methyl 5- bromo-3-indazolecarboxylate withdimethylaminoethylamine.

N (2 dimethylaminopropyl) 3 indazolecarboxamide, M.P. -146 C. (corr.),by reacting diindazolo[2,3, a-2,3',-d]pyrazine-7,14-dione withZ-dirnethylaminopro pylamine.

N dimethylaminoethyl 1 methyl 3 indazolecarboxamide hydrochloride, M.P.199-200 C. (corr.), by reacting 1-methyl-3-indazolecarbonyl chloridewith dimethylaminoethylamine.

Z-diethylaminoethyl 3 -indazolecarboxylate hydrochloride, M.P. 147150 C.(corr.), by reacting diindazolo[2, 3-a,2',3'-d]pyrazine-7,14-dione withdiethylaminoethanol followed by treatment with ethereal hydrogenchloride.

N dimethylaminoethyl 2 methyl 3 indazolecarboxamide hydrochloride, M.P.186 C. (corr.), by reacting 2-methyl-3-indazolecarbonyl chloride withdimethylaminoethylamine.

N [3 (1 piperidyDpropyl] 3 indazolecarboxamide, M.P. l22123 C. (corr.),by reacting diindazolo[2,3-a,2, 3'-d]-Pyrazine-7,14-dione with3-(1-piperidyl)propylamine.

N [2 (4 morpholinyDethyl]-3-indazolecarboxamide, M.P. 169170 C. (corr.),by reacting diindazolo[2,3-a,2', 3 d]pyrazine-7,l4dione with 2 (4morpholinyDethylamine.

N [3 (4-morpholinyl)propyl]-3-indazolecarboxamide, M.P. 162-163 C.(corr.), by reacting diindazolo[2,3-a,2, 3'-d]-pyrazine-7,l4-dione with3-(4-morpholinyl)propylamine.

N [2 (l piperidybethyl] 3 indazolecarboxamide, M.P. 157159 C. (corr.),by reacting diindazolo [2,3-'a,2', 3'-d]PYraZine-7,l4di0ne with2-(l-piperidyDethylamine.

N- [2- 4-methyll-pipera zinyl ethyl] -3 -indazolecarboxamide, M.P.177-l78 C. (corr.), by reacting diindazolo-[2,3-a,2,3'-d]pyrazine-7,14-dione with 2-(1-methyl-4-piperazinylethylamine.

N- [2- (4-phenyll-piperazinyl) ethyl] -3 -indazolecarboxamide, M.P.236237 C. (corr.), by reacting diindazolo-[2,3-a,2',3'-d]pyrazir1e-7,14-dione with2-(4-phenyl-1-piperazinyl)ethylamine.

N-(Z-diethylaminoethyl) 3 indazolecarboxamide hydrochloride, M.P. 169170C. (corr.), by reacting diindazolo[2,3-a,2,3'-d]pyrazine 7,14 dione withdiethylaminoethylamine followed by treatment with ethereal hydrogenchloride.

N-[2-( 1-pyrr0lidyl)e thyl] -3-indazolecarboxamide, M.P. 144-145" C.(corn), by reacting diindazolo[2,3-a,2, 3-d]pyrazine-7,l4-dione with 2-[1-pyrrolidyl]ethylamine.

Z-dimethylamino-l-methylethyl 3-indazolecarboxylate hydrochloride, M.P.217-222 C. (corr.), by reactingdiindazolo[2,3-a,2',3'-d]pyrazine-7,14-dione withdimethylamino-Z-propanol followed by treatment with ethereal hydrogenchloride.

(l-pyrrolidinyl)ethoxyethyl 3-indazoiecarboxylate hydrochloride, MP.146-148 C. (corn), by reactingdiindazolo[2,3-a,2',3'-d]pyarzine-7,l4-dione with(l-pyrrolidinyl)ethoxyethylalcohol followed by treatment with etherealhydrogen chloride.

N-(Z-dimethylamino-1methylethyl) 1 methyl 3 indazolecarboxarnidehydrochloride, M.P. 215-217 C. (corr.), by reacting1methyl-3-indazolecarbonyl chloride with dimethylamino-Z-propanol.

N (2 dimethylamino 1 methylethyl) 3 indazolecarboxamide hydrochloride,MP. 252-255 C. (corn), by reactingdiindazolo[2,3-a,2,3-d]pyraZine-7,14-dione with dimethylamino-Z-propanolfollowed by treatment with ethereal hydrogen chloride.

(l-pyrrolidinyl)ethoxyethyl 1-methyl-3-indazolecarboxylate diphosphate,M.P. 147-148 C. (corn), by eacting 1-methyl-3-indazolecarbonyl chloridewith (l-pyrrolidinyl)etho ;yethylalcohol followed by treatment withphosphoric acid.

N-(Z-dimethylaminoethyl)-5-methoxy-3-indazolecarboX- amidehydrochloride, M.P. 130-132 C. (corn), by reacting 2,9dimethoxydiindazolo[2,3-a,2',3'-d]pyrazine-7,14- dione, M.P. 3l0 C.,with dimethylaminoethylamine followed by treatment with etherealhydrogen chloride.

N-[2-(l-pyrrolidinyl)ethyl] 5 methoxy-3-indazolecarboxamide, MP. 137-139C. (corr.), by reacting 2,9-dimethoxydiindazolo [2,3-a,2,3 -d]pyrazine-7,14-dione with l-pyrrolidinyl)ethylalcohol.

Following the general procedures described above other basic esters andamides of B-indazolecarboxylic acids which can be prepared include forexample, 4-dibutylaminobutyl-l-phenyl 3 indazolecarboxylate by reactingmethyl 1-phenyl-3-indazolecarboxylate with 4-dibutylamino-l-butanol;6-diethylaminohexyl 4-trifluoromethyl- 3-indazolecarboxylate by reactingethyl 4-trifluoromethyl- 3-indazolecarboxylate with 6 diethylamino 1hexanol; N-(3-thiomorpholinopropyl)-1-benzyl-3-indazolecarboxamide byreacting methyl 1-benzyl-3-indazolecarboxylate with3-thiomorpholinopropylamine; 2,6-dimethylpiperidinoethyl3-indazolecarboxylate by reacting diindazolo-[2,3-a,2,3'-d]pyrazine-7,14-dione with 2,6-dimethylpiperidinoethanol;3-diethylaminopropyl 6-methyl-3-indazolecarboxylate by reacting methyl6-methyl-3-indazolecarboxylate with 3-diethylamino-1-propanol; andN-(Z-Inethylethylaminoethyl)-5-nitro-3:indazolecarboxamide by re- Sacting ethyl S-nitro-indazolecarboxylatc with N-methyl-N-ethylethylenediamine.

I claim: 1. A member of the group consisting of a compound having thestructural formula in which Y is a member of the group consisting ofhydrogen, lower-alkyl, lower-alkoxy, lowcr-alkylrnercapto,lower-alkylsulfinyl, lower-alkylsulfonyl, nitro, halogen,trifiuoromethyl, and amino; R is a member of the group consisting ofhydrogen, lower-aliphatic hydrocarbon, phenyl and benzyl; X is a memberof the group consisting of O and NH; Alk is a member of the groupconsisting of alkylene having from two to six carbon atoms and havingthe free valences on different carbon atoms and oxa-alkylene having fromfour to eight carbon atoms; and N:B is a member of the group consistingof di- (lower-alltynarnino, l-pyrrolidinyl,lower-alkylated-lpyrrolidinyl, piperidino, lower-alkylated-pipcridino,morpholino, lower alkylated morpholino, thiomorpholino,lower-alkylated-thiomorpholino, l-piperazinyl, 4-methyll-piperazinyl,4-phenyl 1 piperazinyl, l-hexamethyleni minyl, andl-heptamethyleniminyl, and pharmaceutically acceptable lower-alkyl,lower-alkenyl and monocarbocyclicarylmethyl quaternary ammonium saltsthereof.

2. N-(Z-dimethylaminoethyl) 3 indazolecarboxamide methyltoluenesulfonate.

3. N-[Z-(l hexamethyleniminyl)ethyl] 3 indazole carboxamide methyltoluenesulfonate.

4. N-(Z-dimethylaminoethyl)-3-indazolecarboxamide.

5. N (2dimethylarninoethyl)-2-methyl-3-indazolecarboxarnide.

6. N-(Z-dimethylaminoethyl)-4,5,6,7-tetrahydro-3-indazolecarboxamide.

7. N-[2-(1-pyrrolidinyl)ethyl]-3-indazolecarboxamide.

8. N (2 dimethylaminoethyl)-1-methyl-3-indaz0lecarboxamide.

9. Diethylaminoethoxyethyl 3-idazolecarboxylate.

10. 3-diethylaminopropyl B-indazolecarboxylate.

11. N-[di (lower-alkyDaminoalkyl]-3-indazolecarboxamide.

l2. N-[di (lower-alkyl)arninoalkyl]4,5,6,7-tetrahydro-3-indazolecarboxamide.

References Cited in the file of this patent Smith et 211.: J. Org.Chem., vol. 23, page 621 (1958). Musante et al.: Gazz. Chim. Ital, vol.77, pages 199- 206 (1947).

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,145,215 August 18, 1964 Frederick Kc Kirchner It is hereby certifiedthat error appears in the above numbered patent requiring correction andthat the said Letters Patent should read as corrected below.

Column 2 line 28, for ""-CH(CHH )CH read -CH(CH -)"CH line 34, for"hydrogen" read hydrocarbon column 3, lines 51 and 52, for "dependings"read depending column 7, line 13, for "pyarzine" read pyrazine line 26,for "'eacting" read reacting Signed and sealed this 22nd day of December1964.

(SEAL) Attest:

ERNEST W. SWIDER' EDWARD J. BRENNER Attesting Officer Commissioner ofPatents

1. A MEMBER OF THE GROUP CONSISTING OF A COMPOUND HAVING THE STRUCTURAL FORMULA 